The key function of immune system is to protect the body from infections (for example, viral or bacterial) and malignant neoplasms. The system involves several types of lymphoid and myeloid cells such as monocytes, macrophages, dendrite cells, eosinophils, T-cells, B-cells and neutrophils. These lymphoid and myeloid cells can induce the signal proteins known as cytokines. Inflammation is a part of immune response and causes the accumulation of immune cells, either systemic or centered in certain parts of the body. When responding to the infection or any foreign substance, immune cells release cytokines which, in their turn, modulate immune cell proliferation, development, differentiation and migration. The immune response can induce various pathological processes, for example, if it triggers the excessive inflammation as it happens in case of autoimmune diseases (ref. Abbas et al. (eds.) (2000) Cellular and Molecular Immunology, W.B. Saunders Co., Philadelphia, Pa.; Oppenheim and Feldmann (eds.) (2001) Cytokine Reference, Academic Press, San Diego, Calif.; von Andrian and Mackay (2000) New Engl. J. Med. 343:1020-1034; Davidson and Diamond (2001) New Engl. J. Med. 345:340-350).
Today the IL-17 family includes IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. All members of IL-17 family have four highly conserved cysteine residues which are involved in the formation of inter-chain disulfide bonds, and two or more cysteine residues which also may be involved. Members of IL-17 family have nothing similar to the sequences of other known cytokines.
Interleukin-17A (IL-17A, also known as cytotoxic T-lymphocyte-associated antigen-8 (CTLA-8), IL-17) is a homodimeric cytokine of 20-30 kDa produced by memory T-cells with the following antigen recognition. The growth of these T-cells is promoted by interleukin-23 (IL-23) (McKenzie et al. (2006) Trends Immunol. 27(1):17-23; Langrish et al. (2005) J. Exp. Med. 201(2):233-40). IL-17A acts via two receptors (IL-17RA and IL-17RC) to initiate the production of multiple molecules involved in the processes with neutrophils, inflammatory processes and organ damage. This cytokine is synergetic with tumor necrosis factor (TNF) or interleukin 1-beta (IL-1β) to achieve a more pronounced anti-inflammatory effect. In the therapy of many inflammatory, immune and proliferative conditions including rheumatoid arthritis (RA), osteoarthritis, osteoporosis in patients with RA, inflammatory fibrosis (including scleroderma, pulmonary fibrosis and cirrhosis), gingivitis, periodontitis or periodontal diseases, inflammatory bowel diseases (for example, Crohn's disease, ulcerative colitis and inflammatory bowel disease), asthma (including the allergic asthma), allergies, chronic obstructive pulmonary disease (COPD), multiple sclerosis, psoriasis, cancer and other disorders it was proposed to reduce IL-17A activity by means of antibodies or antigen-binding antibody fragments which block said receptors (for example, refer to US 2003/0166862, WO 2005/108616, WO 2005/051422 and WO 2006/013107).
At the present time, several types of anti-IL-17 antibodies were developed including AIN457 (secukinumab by Abbott Laboratories), LY2439821 (Ixekizumab by Eli Lilly), SCH900117 (Merck), RG4943 (Roche), etc.
For example, the US Patent application US 2010/0245666 describes anti-IL-17 antibody (secukinumab, AIN457) that contains an amino acid substitution or deletion in one of CDR regions of the heavy or light chains. This antibody is highly affine to IL-17 with dissociation constant KD of about 122 μM. This application also discloses the use of said antibodies to inhibit IL-17 binding with an appropriate receptor, especially for the treatment of uveitis. Currently, the said antibody undergoes the clinical trials for the treatment of RA, ankylosing spondyloarthropathy, Crohn's disease, psoriasis, multiple sclerosis and ozone-induced neutrophilia. It was shown that this antibody is safe and exhibits 46% efficacy in patients with RA (Durez et al., Communication EULAR 2009-RA).
The prior knowledge has also disclosed the humanized antibodies against IL-17 as described in the international publication of WO 2007/070750 application (LY2439821, ixekizumab, Eli Lilly). Said antibodies contain variable heavy and light chain domains with amino acid substitutions. Upon that, the said antibody is highly affine to human IL-17 (KD is lower than about 7.0-4.0 pM) and has koff index for human IL-17<2×10−5 sec−1. Antibodies were subject clinical studies of the safety, tolerability and efficacy upon intravenous administration in subjects with RA. (Genoevse et al., Communication EULAR 2009-RA; Genoevse et al., Arthritis & Rheumatism, 62: 929-39, (2010).
The prior state of art has information on other anti-IL-17 antibodies: murine anti-human neutralizing antibodies eBio64CAP17 (eBioscience) and derivatives thereof. Other examples of anti-IL-17 antibodies were disclosed in patent applications US2009/0175881A1 and US2008/0269467A1, and in international publications WO2008/001063A1 and WO2007/117749A1.
Thus, taking into account its localized expansion in the area of inflammation, IL-17 is a new target in the therapy of inflammatory and autoimmune disorders, with the safety profile potentially higher than drugs targeting the systemic circulation proinflammatory cytokines such as TNF (tumor necrosis factor). In view of the above said, it can be concluded that there is a need for antibodies having antagonistic activity or neutralizing the activity of IL-17A for treating the diseases and conditions, wherein the biological activity of IL-17A causes or promotes the adverse pathological result, or diseases and conditions, wherein the reduction of IL-17 biological activity promotes the desirable therapeutic result, including inflammatory disorders, cell proliferative and developmental disorders, autoimmune pathologies such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).
The largest limitations of using antibodies as medicinal agents are due to their immunogenicity and affinity. Since the majority of monoclonal antibodies are obtained on the basis of murine ones, the regular use of such antibodies in humans causes the development of immune response to antibody therapy (for example, allergic reactions). These types of immune response finally result in the lack of efficacy at least, and in potential anaphylactic reactions at worst.
Thus, the present invention suggests anti-IL-17 antibodies with amino acid substitutions, wherein the claimed antibodies possess high affinity, improved solubility and increased IC50.